Gona-4,9(10)-dienes and process of producing the same

ABSTRACT

New gona-4,9(10)-dienes of formula I ##STR1## where R is alkyl of 1 to 3 carbon atoms and X is Cl, Br, F, N 3 , SCN, CN, OH, OR&#39;(R&#39;-alkyl), NH 2 , a substituted amino group or a heterocyclic compound including nitrogen in the ring. The compounds have valuable biological properties, especially hormonal and antihormonal effects, and can be used to advantage in pharmaceutical preparation, for the treatment of endocrinopathies and for reproduction control in human beings and livestock. 
     The invention also embraces a process for making the compounds by converting 3-methoxy-13β-R-gona-2,5(10)-diene-17β-spiro-1,`2`-oxiranes to 17β-hydroxy-17α-CH 2  -13β-R-gona-4,9(10)-diene-3-ones to the 17α-CH 2  X-14β-ols which are hydrolyzed to the 17β-OH which latter are then converted to the compounds of formula I.

This is a continuation, of application Ser. No. 816,871, filed July 18,1978, which in turn is a continuation-in-part of application Ser. No.806,471, filed June 14, 1977, both now abandoned.

BACKGROUND OF THE INVENTION

The compounds that can be produced by the process according to theinvention are new; their synthesis has not been described yet.

The object of the invention is the production of gona-4,9(10)-dienesaccording to formula I below, which in terms of biological effects aresuperior to comparable compounds of the prior art which are accepted inmedical therapy.

The invention also has the object of providing a technologicallyimplementable and economically acceptable process for the production ofthe gona-4,9(10)-dienes.

SUMMARY OF THE INVENTION

These objects are met in the following way:

3-methoxy-13β-R-gona-2,5(10)-diene-17β-spiro-1,`2`-oxiranes of formulaII below are opened up by appropriate nucleophilic agents in organicsolvents at ordinary or elevated temperature so as to form thecorresponding 3-methoxy-17α-CH₂ X-13β-R-gona-2,5(10)-diene-17β-ols offormula III below, which in turn are hydrolyzed by a weak acid catalystto 17β-hydroxy-17α-CH₂ X-13β-R-gona-5(10)-ene-3-ones of formula IV belowand converted into the 17β-hydroxy-17α-CH₂X-13β-R-gona-4,9(10)-diene-3-ones of formula I below by treatment with ahalogenation agent and subsequent dehydrohalogenation. In these formulaeR is alkyl of 1 to 3 carbon atoms and X is Cl, Br, F, N₃, SCN, CN, OH,OR'(R'═alkyl), NH₂, a substituted amino group or a heterocyclic compoundincluding nitrogen in the ring.

The individual reaction steps of the process are further explained bythe following sequence of formulae: ##STR2##

DETAILS AND PREFERRED EMBODIMENTS

The spiro oxiranes of formula II used as starting products are known.They can be produced, for instance, according to Deutsche DemokratischeRepublik, (Wirtschafts) Patent 80 023. Sodium oxide, alkali cyanides,alkali alkoxides, alkali hydroxides, ammonia, primary and secondaryamines, and nitrogenous heterocyclic compounds are preferablenucleophilic agents for the first step, which is performed under neutralor alkaline conditions.

Selection of the solvent depends on the solubility of the spiro oxirane(II) and the nucleophilic agent used and can be varied within widelimits, the object in general being a homogeneous reaction mixture.Suitable solvents are, for instance, ether, dimethylsulphoxide, ethyleneglycol, ethylene glycol ether, dimethylformamide, and lower alcohols, towhich minor amounts of water may be added.

The temperature at which the reaction is performed can be varied withinrelatively wide limits but is preferably between about 20° C. and 100°C. The opening up of the spiro oxiranes by ammonia, primary andsecondary amines and nitrogenous heterocyclic compounds can in manycases be accelerated by catalytic action obtained by admixture of slightquantities of a weak acid, preferably acetic acid.

Various acid catalysts are suitable for hydrolysis of the enolethers(III). Organic carboxylic acids such as acetic acid, oxalic acid, citricacid or succinic acid in dilute aqueous solution are preferably used,but dilute mineral acids such as hydrobromic acid or perchloric acid arealso suitable.

Selection of the solvent depends on solubility of the substance to behydrolyzed, with organic aqueous solvents, miscible with water, such asalcohols, dioxane or acetone, being generally preferred. It is, however,also possible, to perform the reaction in a mixture of water, a solventmiscible with water, and a solvent not miscible with water, such aswater-methanol-benzene mixtures or water-tertiary butanol-methylenechloride mixtures, with the contents of the individual components ingeneral being selected so that a homogenous phase results. Thehydrolysis can, however, also be performed in a two-phase system.

The halogenation of the Δ⁵(10) -unsaturated 3-ketones (IV) obtained ispreferably performed in an inert solvent at low temperature, e.g. -5° C.to +5° C. Elementary bromine is preferably used, but also perbromidessuch as phenyltrimethylammoniumperbromide or pyridiniumperbromide, andother halogenating agents can be used. Suitable solvents are especiallychlorinated aliphatic hydrocarbons such as methylene chloride, carbontetrachloride and chloroform, but also tertiary organic nitrogenousbases such as pyridine, possibly together with the solvents stated, canbe used. Tertiary organic bases such as pyridine, the picolines,collidine, ethyl pyridine, etc., are preferred as dehydrohalogenatingagents. The process is performed to advantage at room temperature butpossibly the dehydrohalogenation can be accelerated by slight warming.

In general, the process according to the invention is performed so thathalogenation and dehydrohalogenation are executed in one reaction stepwithout intermediate isolation of the halogenation products. Inprinciple, however, it is also possible to produce and isolate thecorresponding 5,10-dihalo compounds in some other conventional manner,and convert them by dehydrohalogenation (halogen acid removal) in asubsequent reaction step to the 4,9(10)-dienes. The compounds of formulaI obtained in the process according to the invention are isolated andpurified by conventional methods.

As a variation of the process according to the invention, conversion ofthe spiro oxiranes (II) by the nucleophilic agents is performed not, asstated above, in neutral or alkaline medium but in faintly acid medium.In that case, hydrolysis of the enolether group in 3-position isperformed concurrently with the spiro epoxide being opened up underintroduction of the 17α-CH₂ X-substituent, and the 17β-hydroxy-17α-CH₂X-13β-R-gona-5(10)-ene-3-one (IV) are obtained in one reaction step.This process variant can be used to special advantage in the productionof formula I compounds where X, for instance, stands for Br, Cl or SCN.For that purpose, the spiro epoxides are dissolved in a suitablesolvent, preferably dimethylformamide, methylene chloride, ether, ordimethylsulphoxide, and treated with dilute solution of hydrochloricacid, hydrobromic acid or rhodanic acid in the same solvent. The Δ⁵(10)-diene-3-ketones (IV) obtained by this process are isolated and purifiedaccording to conventional methods.

Progestational activities are determined according to the McPhail method(R. I. Dorfmann: Methods in Hormone Research, Vol. II, Academic PressNew York and London 1962). The extent of the secretory (transformatory)conversion of the endometrium of infantile rabbits, which was evaluatedaccording to McPhail in steps from 0 to 4 to an accuracy of 0.5 units,was taken as the parameter of progestational activity. Activity wasspecified in the McPhail test in terms of the ED (McPhail 2), defined asthe total dose in mg/kg that caused a transformation of the proliferatedendometrium according to stage 2. The McPhail data were checked with theKruskal-Wallis test. The significance statements refer to comparison ofthe individual groups with the Dunn test.

Table 1 shows the results of the McPhail test, after oral application,for several characteristic representatives of the compounds of theinvention. Table 2 contrasts these data, along with those obtained aftersubcutaneous application, with the ED (McPhail 2) data of some selectedstandard progestational compounds.

It is apparent that, for instance, the two compounds of general formulaI where X═CN, R═CH₃, and X═N₃, R═CH₃, are highly efficientprogestational compounds with oral and subcutaneous applications. Whenapplied orally, the most effective of them (X═CN, R═CH₃) is, in terms ofED (McPhail 2), about 200 times more effective thannorethisteroneacetate, 58 times more effective than ethinodioldiacetate,and 9 times more effective than d-norgestrel.

                                      TABLE 1                                     __________________________________________________________________________    Progestational activity of compounds of general formula I                     in case of oral application                                                                            PcPhail                                                                            Significance                                                   Total dose                                                                              value                                                                              compared to                                                                           Variations                                                                            ED(McPahil 2)                   Compound   Group                                                                             (4d)mg/kg BW                                                                          n X    group   Scope   mg/kg                           __________________________________________________________________________    Sesame oil 1   --      6 0    --      0                                       I, X = N.sub.3, R = CH.sub.3                                                             2   0.05    6 1.33         1.0-1.5                                 "          3   0.10    6 1.58 1(+);2(+);                                                                            1.0-2.5 0.4                             "          4   0.20    6 1.92 1(+++);3(+);                                                                          1.0-2.5                                 "          5   0.40    5 2.00 1(+);4(+);                                                                            1.5-3.0                                 I, X = CN, R = CH.sub.3                                                                  6    0.025  6 0.50 1(+)      0-1.0                                 "          7   0.05    6 2.00 1(+);9(+);                                                                            1.5-3.0 0.05                            "          8   0.10    6 2.58 1(+); 7(+);                                                                           1.5-3.0                                 "          9   0.20    6 2.91 1(+);8(+++);                                                                          2.5-3.5                                 __________________________________________________________________________     BW = body weight                                                              n = number of test animals                                                    d = day                                                                  

                  TABLE 2                                                         ______________________________________                                        Comparison of progestational activities of                                    selected steroids in case of oral and subcut-                                 aneous application                                                                           ED(McPhail 2) mg/kg BW                                         Compound       p.o.          s.c.                                             ______________________________________                                        Norethisterone --            5.55+                                            Norethisteroneacetate                                                                        >10           --                                               Ethinodioldiacetate                                                                          2.9           --                                               d-norgestrel   0.45          0.25+                                            I, X = N.sub.3, R = CH.sub.3                                                                 0.40          0.105                                            I, X = CN, R = CH.sub.3                                                                      0.05          >0.01                                            ______________________________________                                         +according to R. A. Edgren et al., Int. J. Fert., Vol. 11, p 389 (1969)  

The embodiments described below are to explain the process according tothe invention without restricting it in any way.

EXAMPLE 1

17α-azidomethyl-17β-hydroxy-13β-methyl-gona-4,9(10)-diene-3-one.

1st stage: 3.0 g (0.01 mole) of3-methoxy-13β-methyl-gona-2,5(10)-diene-17β-spiro-1,`2`-oxirane aresuspended in 200 ml of ethylene glycol and, after addition of 5.0 g ofsodium azide, heated for 6 hours on boiling water bath. The steroiddissolves at first and precipitates again with progressing reaction. Thepreparation is cooled and then poured into about 1,500 ml of ice water.The colorless crude product is sucked off and thoroughly washed withwater. Recrystallization from methanol yields colorless needles with amelting point at 123° to 124° C., [α]_(D) ²⁵ +81° (C=0.5 chloroform).

Yield: 3.30 g (95 percent).

2nd stage: 1.72 g (0.005 mole) of the17α-azidomethyl-13β-methyl-3-methoxy-gona-2,5(10)-diene-17.beta.-olobtained in the preceding stage are suspended in 100 ml of methanol, anda solution of 1.0 g of oxalic acid in 5 ml of water is added while cold.When shaken from time to time, the substance dissolves completely withinabout 90 minutes. After 2 hours the solution is poured into ice water,the flocculent crude product is sucked off, washed thoroughly withwater, and dried in the desiccator. The yield is 1.42 g (85 percent).

Recrystallization from isopropyl ether yields an analytically pureproduct with melting point at 105° C., [α]_(D) ²⁵ +119° (C=0.5chloroform).

3rd stage: 1.32 g (0.004 mole) of the17α-azidomethyl-17β-hydroxy-13β-methyl-gona-5(10)ene-3-one obtained inthe preceding stage are dissolved in 10 ml of pyridine, cooled to 5° to10° C. and mixed with a solution of 1.5 g of pyridiniumperbromide in 12ml of pyridine. The preparation is first stirred for 30 minutes at thattemperature, then for 2 to 4 hours at room temperature, and at lastpoured into 100 ml of ice-cooled 2 n hydrochloric acid. The precipitatedyellowish crude product is sucked off, thoroughly washed with water and,while still humid, recrystallized from methanol.17α-azidomethyl-17β-hydroxy-13β-methyl-gona-4,9(10)-diene-3-one formscolorless needles with melting point at 204° to 206° C., [α]_(D) ²⁵-250° (C=0.5 chloroform).

Yield: 0.48 g (30 percent).

EXAMPLE 2

17α-azidomethyl-17β-hydroxy-13β-ethyl-gona-4,9(10)-diene-3-one.

1st stage: 0.943 g (0.003 mole) of13β-ethyl-3-methoxy-gona-2,5(10)-diene-17β-spiro-1,`2`-oxirane aresuspended in 70 ml of ethylene glycol, and 1.5 g of sodium azide areadded. Then, the preparation is heated for about 100 hours on a boilingwater bath, allowed to cool and then poured into about 1,000 ml ofwater. The colorless flocculent product is sucked off, washed thoroughlywith water and, while still humid, recrystallized from methanol,yielding colorless needles with melting point at 157° to 159° C.,[α]_(D) ²⁵ +77° (C=0.5 chloroform).

Yield: 0.72 g (61 percent).

2nd stage: 2.8 g (0.008 mole) of the17α-azidomethyl-13β-ethyl-3-methoxy-gona-2,5(10)-diene-17β-ol describedabove are dissolved in 6 ml of benzene and mixed with 30 ml of methanol.1.5 g of oxalic acid dihydrate in saturated aqueous solution are added,and the preparation is intensively stirred. After 1 to 2 hours thereaction is complete, then water and benzene are added, and the layersare separated. The aqueous phase is repeatedly extracted with benzene,and the combined extracts are washed with bicarbonate solution andwater. The preparation is then dried over sodium sulphate, and thesolvent is expelled in vacuum. The remaining yellow oil is absorbed inhot acetonitrile. Cooling results in colorless prisms with melting pointat 121° to 123° C., [α]_(D) ²⁵ +116.5° (C=0.5 chloroform).

Yield: 1.65 g (60 percent).

3rd stage: 3.1 g (0.009 mole) of the17α-azidomethyl-17β-hydroxy-13β-ethyl-gona-5(10)-ene-3-one- describedabove are dissolved in 50 ml of pyridine and cooled to 0° C. 1.58 g ofbromine, dissolved in 10 ml of methanol, are added to the solutiondropwise. The solution is stirred for 30 minutes at 0° C., then for 3 to4 hours at room temperature, and then poured into about 1,000 ml ofice-cold 2 n hydrochloric acid. The colorless flocculent crude productis sucked off, thoroughly washed with water, and dried. It is dissolvedin a minimum of chloroform at boiling point and then filtered. Aftercooling, the same or up to double the quantity of methanol is added.17α-azidomethyl-17β-hydroxy-13β-ethyl-gona-4,9(10)-diene-3-onecrystallizes in small prisms with melting point at 223° to 226° C.,[α]_(D) ²⁵ -224° (C=0.5 pyridine).

Yield: 2.26 g (73 percent).

EXAMPLE 3

17α-cyanomethyl-17β-hydroxy-13β-methyl-gona-4,9(10)-diene-3-one.

1st stage: 15.0 g (0.05 mole) of3-methoxy-13β-methyl-gona-2,5(10)-diene-17β-spiro-1,`2`-oxirane aredissolved in 500 ml of ethanol and mixed with a solution of 50 g ofpotassium cyanide in 100 ml of water. The solution is stirred at roomtemperature until the thin-layer chromatogram does not any longerindicate the presence of any starting material, which process will takeabout 2 days. The mass is then cautiously mixed with 200 to 300 ml ofwater and left standing overnight. The precipitated product is suckedoff, washed carefully, and dried in the open air. Recrystallization fromacetonitrile yields colorless crystals, which melt at 145° to 151° C.and contain 1/2 mole of crystal ethanol.

Yield: 10.7 g (61 percent).

2nd stage: 9.8 g (0.03 mole) of the17α-cyanomethyl-13β-methyl-3-methoxy-gona-2,5(10)-diene-17.beta.-olobtained according to the foregoing procedure are suspended in 400 ml ofmethanol and mixed with a solution of 4.0 g of oxalic acid dihydrate in25 ml of water. The preparation is stirred at room temperature untilthere is no residue and starting compound is no longer indicated in thethin-layer chromatogram (3 to 6 hours). The preparation is poured intoabout 2,000 ml of ice water and left standing overnight. The colorlessflocculent product is sucked off and dried on the air. It issufficiently pure for further conversion.

Yield: 8.5 g (90 percent).

An analytically pure product is obtained by recrystallization from85-percent isopropanol. Melting point at 167° to 169° C., [α]_(D) ²⁵+155.4°, (C=0.5 chloroform).

3rd stage: 3.44 g (0.011 mole) of the17α-cyanomethyl-17β-hydroxy-13β-methyl-gona-5(10)-ene-3-one obtained inthe preceding stage are dissolved in 15 ml of pyridine and slowly mixedwith a solution of 4.0 g of pyridiniumperbromide in 35 ml of pyridine.The preparation is stirred for 90 minutes at room temperature, and thereaction mixture is then poured into about 400 ml of ice-cold 2 nhydrochloric acid. The yellowish flocculent product is sucked off,thoroughly washed with water, and dried in air. Crude yield: 2.35 g.Recrystallization from acetic ester and 80-percent acetonitrile yieldsneedles with melting point at 204° to 214° C., [α]_(D) ²⁵ -290° (C=0.5pyridine).

Yield: 1.4 g (32 percent).

EXAMPLE 4

17α-bromomethyl-17β-hydroxy-13β-methyl-gona-4,9(10)-diene-3one.

1st stage: 5.96 g (0.02 mole) of3-methoxy-13β-methyl-gona-2,5(10)-diene-17β-spiro-1,`2`-oxirane aredissolved in 200 ml of dimethylformamide, and then 5 ml of 48 percenthydrobromic acid in 50 ml of the same solvent are added in one step. Thesolution is stirred for 2 minutes and then immediately poured into about1,000 ml of ice water. The colorless flocculent product is sucked off,amply washed with water, and dried in the air. Recrystallization frombenzene yields colorless crystals with melting point at 127° to 129° C.,[α]_(D) ²⁵ +109° (C=0.5 chloroform).

Yield: 4.1 g (56 percent).

2nd stage: 1.1 g (0.003 mole) of the17α-bromomethyl-17β-hydroxy-13β-methyl-gona-5(10)-ene-3-one obtained inthe preceding stage are dissolved in 20 ml of pyridine and cooled to 0°C. The solution is stirred and a solution of 0.60 g of bromine in 5 mlmethanol is slowly added dropwise. Stirring continues for 30 minutes at0° C. and then from 2 to 4 hours at room temperature. Thereafter thesolution is stirred into 500 ml of ice-cold 2 n hydrochloric acid. Thefaintly yellowish flocculent product is sucked off, washed with water,and dried in the desiccator. Recrystallization from 90 percentacetonitrile yields17α-bromomethyl-17β-hydroxy-13β-methyl-gona-4,9(10)-diene in the form ofsturdy prisms with melting point at 119° to 123° C., [α]_(D) ²⁵ -271.3°C. (C=0.5 chloroform).

Yield: 0.41 g (37 percent).

Without further analysis, the foregoing will so fully reveal the gist ofthe present invention that others can, by applying current knowledge,readily adapt it for various applications without omitting featuresthat, from the standpoint of prior art, fairly constitute essentialcharacteristics of the generic or specific aspects of this invention.

What is claimed as new and desired to be protected by Letters Patent isset forth in the appended claims.
 1. A compound of the formula ##STR3##wherein R is methyl and X is Cl, or Br, or R is ethyl and X is Cl, Br,N₃ or CN.
 2. The compound of claim 1 which is17α-azidomethyl-17β-hydroxy-13β-ethyl-gona-4,9(10)-diene-3-one.
 3. Thecompound of claim 1 which is17α-bromomethyl-17β-hydroxy-13β-methyl-gona-4,9(10)-diene-3-one.
 4. Aprocess for producing gona-4,9(10)-dienes comprising(a) opening up a3-methoxy-13β-R-gona-2,5(10)-diene-17β-spiro-1',2'-oxirane of theformula ##STR4## by reaction with a nucleophilic agent selected from thegroup consisting of hydrobromic acid, hydrochloric acid, sodium azide,alkali cyanides, ammonia and primary or secondary amines in an organicsolvent so as to form the corresponding 3-methoxy-17α-CH₂X-13β-R-gona-2,5(10)-diene-17β-ol of the formula ##STR5## then (b)hydrolyzing the latter compound with a slightly acidic catalystconstituted by a weak organic carboxylic acid in dilute aqueous solutionor by a dilute mineral acid whereby the 17β-hydroxy-17α-CH₂X-13β-R-gona-5(10)-ene-3-ol of the formula ##STR6## is formed,thereafter (c) converting the latter compound by reaction with ahalogenating agent into the 5,10-dihalogenated compound, and (d)subjecting the dihalogenated compound to dehydrohalogenation, therebyforming a 17β-hydroxy-17α-CH₂ X-13β-R-gona-4,9(10)-diene-3-one, whereinR is methyl or ethyl and X is Br, Cl, N₃ or CN.
 5. The process of claim4 wherein the reaction is performed under neutral or alkalineconditions.
 6. The process of claim 4 wherein the organic solvent is alower alcohol, ethylene glycol, ether, ethylene glycol ether,dimethylsulphoxide, or dimethylformamide.
 7. The process of claim 4wherein the reaction with the nucleophilic agent is carried out in aslightly acid medium and the hydrolysis of the enol ether group in the3-position is simultaneously carried out with the opening up of theepoxide group and introduction of the 17α-CH₂ X group.
 8. The process ofclaim 4 wherein the hydrolysis is performed in the presence of theslightly acidic medium in an organic solvent that is miscible with wateror in a solvent mixture between water, a water-miscible solvent and anonwater-miscible solvent.
 9. The process of claim 8 wherein thehydrolysis reaction is carried out in an alcohol, dioxane, acetone, amixture of water with methanol and benzene or a mixture of water withtertiary butanol and methylene chloride.
 10. The process of claim 4wherein the catalyst for the hydrolysis is acetic acid, oxalic acid,citric acid, succinic acid, dilute hydrobromic acid or dilute perchloricacid.
 11. The process of claim 4 wherein the halogenating reaction iscarried out by reaction with bromine or a perbromide in a chlorinatedaliphatic hydrocarbon solvent or a tertiary organic nitrogen containingbase.
 12. The process of claim 4 wherein the halogenating reaction iscarried out in the presence of phenyltrimethylammoniumperbromide orpyridiniumperbromide at a temperature between -5° and +10° C. in aninert solvent.
 13. The process of claim 12 wherein the solvent is achlorinated aliphatic hydrocarbon or a tertiary organic nitrogenousbase.
 14. The process of claim 14 wherein the dehydrohalogenation iscarried out by reaction with a tertiary organic base at room temperatureor a slightly elevated temperature.
 15. The process of claim 14 whereinthe tertiary organic base is pyridine, a picoline, collidine or ethylpyridine.
 16. A process as defined in claim 4, wherein in the reactionat (a) the solution is formed in dimethylformamide, methylene chloride,ether or dimethylsulfide as solvent, whereupon the solution is subjectedto the action of hydrochloric acid or hydrobromic acid before adding theacid catalyst for the hydrolysis reaction.
 17. A process as defined inclaim 4, wherein the reaction with the nucleophilic agent is carried outat a temperature of between about 20° and 100° C. in the presence of aweak acid as catalyst.